In this .project, we have been testing the hypothesis that neuroinflammation contributes to[unreadable] neurodegeneration in vivo and that targeting selective glial activation pathways linked to disease-relevant[unreadable] endpoints will suppress neuroinflammation and provide neuroprotection. We emphasize throughout this[unreadable] application by concrete examples how our work has contributed to a better understanding of molecular[unreadable] mechanisms underlying neuroinflammation, how our in vivo studies have validated the relationship between[unreadable] chronic glial activation and neuronal dysfunction/death, and how our in vivo (integrated) chemical biology[unreadable] research has demonstrated that targeting neuroinflammatory signaling pathways is a viable approach to[unreadable] development of future therapeutics for Alzheimer's disease (AD). Our work over the last four years has[unreadable] contributed substantially to the increasing appreciation of the field that neuroinflammation plays a key role in[unreadable] the progression of pathology in neurodegenerative diseases, and we are committed and eager to continue our[unreadable] work in this area. Finally, MERIT grant awardees are expected to be leaders in their disciplines, and to increase[unreadable] their visibility and contributions to the field during the time of the award. During the last four years, I believe[unreadable] that this has been the case in terms of my contributions to the area of neuroinflammation and AD.[unreadable] The specific aims of the current funding period relate to this two-pronged research effort of defining[unreadable] mechanisms and developing strategies for modulation of glial activation. The goal of aim 1 was elucidation of[unreadable] molecular mechanisms of glial activation induced by beta-amyloid 1-42 (A(3) as the prototypical AD-relevant,[unreadable] glial activating stimulus. The goal of aim 2 was to develop strategies to modulate glial activation pathways that[unreadable] lead to detrimental responses and examine the consequences to neuronal function[unreadable]